tbuckley/cabot-search huggingface dataset:
Abstract 1236: Direct interaction between cancer cells and fibroblasts drives epithelial-to-mesenchymal plasticity (EMP)
Authors: Nilu Dhungel, Ana-Maria Dragoi
Journal: Cancer Research (2023)

Abstract The tumor microenvironment (TME), composed of immune cells and fibroblasts, blood vessels, signaling molecules and extracellular matrix, is the source of important cues that govern epithelial-to-mesenchymal (EMT) transition and facilitate the acquisition of aggressive traits by cancer cells. It is now recognized that EMT is not a binary program, and cancer cells rarely switch to a fully mesenchymal phenotype. Rather, cancer cells exist in multiple hybrid epithelial/mesenchymal (E/M) states responsible for cell population heterogeneity, which is advantageous for the ever-changing environment during tumor development and metastasis. How are these hybrid states generated and maintained is not fully understood. We show that direct interaction between small cell lung carcinoma cells (SCLC) and lung fibroblasts induces a hybrid EMT phenotype in cancer cells in which several mesenchymal genes involved in receptor interaction with the extracellular matrix (ECM) and ECM remodeling are upregulated while epithelial genes such as E-cadherin remain unchanged. We also demonstrate that several core EMT-regulating transcription factors (EMT-TFs) are upregulated in cancer cells during direct contact with fibroblasts, as is Yes-associated protein (YAP1), a major regulator of the Hippo pathway. Further, we show that these changes are transient and reverse to the initial state once the interaction is disrupted. Altogether, our results provide evidence that tumor cells’ direct contact with the fibroblasts in the TME initiates a signaling cascade responsible for hybrid E/M states of cancer cells. These hybrid states are maintained during the interaction and possibly contribute to therapy resistance and immune evasion, while interference with direct contact will result in slow recovery and a switch to the initial states. Citation Format: Nilu Dhungel, Ana-Maria Dragoi. Direct interaction between cancer cells and fibroblasts drives epithelial-to-mesenchymal plasticity (EMP) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1236.
Abstract 3031: Pilot study of EGFR inhibition with erlotinib in liver fibrosis for hepatocellular carcinoma prevention
Authors: Kenneth K. Tanabe, David Zahrieh, Carrie A. Strand, Yujin Hoshida, Thomas J. Flotte, Gary Della’Zanna, Asad Umar, Paul Limburg
Journal: Cancer Research (2023)

Abstract BACKGROUND: Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. Data from preclinical models strongly support epidermal growth factor receptor (EGFR) as a target for chemoprevention of HCC. Erlotinib is a small-molecular EGFR tyrosine kinase inhibitor that is FDA-approved for cancer treatment. The side effects of erlotinib observed in patients receiving the oncology dose (150 mg/day) render it unacceptable as a chemoprevention agent at this dose. OBJECTIVE: The objective of this clinical trial was determination of a safe and minimum effective dose of erlortinib for which a ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed. RESULTS: 46 participants were pre-registered and 25 participants were registered in this multicenter trial. In a dose de-escalation trial design, cohorts of participants received a 7 day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib. A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. A favorable modulation of the Prognostic Liver Signature was observed in participants that received the higher erlotinib doses (50 and 75 mg/day). CONCLUSION: These data support the selection a dose of 25 mg/day of erlotinib for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug. Citation Format: Kenneth K. Tanabe, David Zahrieh, Carrie A. Strand, Yujin Hoshida, Thomas J. Flotte, Gary Della’Zanna, Asad Umar, Paul Limburg. Pilot study of EGFR inhibition with erlotinib in liver fibrosis for hepatocellular carcinoma prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3031.
Abstract 2760: Evaluation of functional heterogeneity in the potent responses of single CAR-T effector cells
Authors: Benjamin Yellen
Journal: Cancer Research (2023)

Abstract Over the last decade, chimeric antigen receptor (CAR)-T cell immunotherapies have produced some miraculous cures in advanced stage, aggressive leukemias and lymphomas in both children and adults. However, many barriers continue to limit the availability and effectiveness of these therapies, including the lack of reliable potency assays for these cell-based “living” medicines. Unlike molecular medicines, which have well established manufacturing processes, cell based medicines are inherently heterogeneous, and each engineered lot of cells will inevitably have a distribution of growth properties, cytolytic activity, gene expression patterns, and secretion profiles, and it is not clear which cell subpopulations are most correlated with positive clinical outcomes.Here we report results of an evaluation of phenotypic heterogeneity in a population of anti-CD19 CAR-T cells co-cultured with target cells in an array of &amp;gt;300,000 microwells. Our approach uses high throughput time lapse imaging to continually monitor the cell-cell interactions between effector and target cells. We maintained cell viability in the microwells for more than 5 days, which gave us sufficient time to observe the full range of antigen-mediated cell killing phenotypes, and also evaluate growth rates of the potent effector cells. We tracked thousands of individual co-cultures through time lapse imaging, and cell behavior was evaluated and sorted by deep learning algorithms. We were able to quickly identify and retrieve clones that exhibited desirable phenotypes for full molecular characterization.Our analysis shows that three fundamental subpopulations of effector cells can be clearly distinguished and quantified. These are 1) effector cells that kill the targets and then die, 2) effector cells that kill the target and then proliferate, and 3) effector cells that do not kill the target. We further dissect these populations by characterizing their secretion and transcriptomic profiles, to identify further subtype classifications. Citation Format: Benjamin Yellen. Evaluation of functional heterogeneity in the potent responses of single CAR-T effector cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2760.
Abstract 6144: Polyploidization enables initial survival of chemotherapy but a progressively increased susceptibility to ferroptosis
Authors: Luke Loftus
Journal: Cancer Research (2023)

Abstract Once cancer has metastasized it remains incurable owing to evolved resistance to nearly all systemic therapies. Classical views of therapeutic resistance include tumor heterogeneity and genetic instability, but our group and others have identified an unappreciated cancer cell phenotype, the polyaneuploid cancer cell (PACC) state, that provides an alternative model. The PACC state is induced upon exposure to a variety of applied stressors, including multiple different classes of chemotherapy, and is characterized by polyploidization of the aneuploid cancer genome. We have shown that this polyploidization is accomplished through endocycling that leads to an enlarged cell size with increased transcriptomic and protein content, higher oxidative buffer capacity, and increased autophagy. We have demonstrated that PACCs are present in a variety of cell lines, arise in response to multiple stressors in vitro, and are resistant to subsequent treatment with several classes of chemotherapy. Thus, we hypothesize that the PACC state is driving therapeutic resistance to current treatment regimens. Elimination of this overlooked phenotype is critical for sustained anticancer therapy response. Cancer cells, including those in the PACC state, control canonical cell cycle and cell death programs to evade apoptosis from external stressors including chemotherapy, highlighting an opportunity to leverage cell cycle-independent death pathways as an alternative therapeutic strategy1. Ferroptosis is a cell cycle agnostic immunogenic form of cell death that is an ideal pathway for elimination of cells in the PACC state. Characterization of ROS levels, glutathione content, labile iron homeostasis, and lipid content indicate that cells in the PACC state have a mounting susceptibility to ferroptosis. Our data suggests that cells in the PACC state keep ferroptosis in check through elevated levels of reduced glutathione and proficient redox activity, including turn over of GPX4, the sole enzyme counteracting lipid peroxidation. Direct inhibition of GPX4 is highly toxic to cells in the PACC state, particularly at later timepoints post therapy removal when the immediate stress response is largely resolved. These studies will directly lead to development of a therapeutic strategy specifically targeting the PACC state with the intention of eliminating cancer resistance. 1Loftus, L.V.; Amend, S.R.; Pienta, K.J. Interplay between Cell Death and Cell Proliferation Reveals New Strategies for Cancer Therapy. Int. J. Mol. Sci. 2022, 23, 4723. https://doi.org/10.3390/ijms23094723 Citation Format: Luke Loftus. Polyploidization enables initial survival of chemotherapy but a progressively increased susceptibility to ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6144.
Abstract 1879: A novel dual CAB nectin-4 x CD3 bispecific antibody targeting solid tumors
Authors: Matthew Lucas, Ana Paula Cugnetti, Haizhen Liu, Charles Xing, Jing Wang, Patricia McNeeley, Christina Wheeler, Solmarie Joyner, Kyrie Johnson, Kathryn Woodard, Wei Zhou, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short
Journal: Cancer Research (2023)

Abstract Nectin-4 is a Ca2+ independent immunoglobulin-like protein that is primarily involved in cell-cell adhesion. Nectin-4 is overexpressed in several tumor types, including breast, lung, urothelial, colorectal, pancreatic, and ovarian cancers. Overexpression of Nectin-4 is associated with multiple aspects of tumor progression such as proliferation, angiogenesis, epithelial to mesenchymal transition, metastasis, DNA repair and tumor relapse. This overexpression is correlated with poor prognosis, making Nectin-4 an attractive target for developing new therapeutic strategies for cancer. As a result, a substantial number of antibody drug conjugates targeting Nectin-4 are under development. Most of these therapies, however, display a high rate of drug related toxicities accentuating the need for alternative approaches for anti-cancer therapeutics targeting Nectin-4. We leveraged BioAtla’s Conditionally Active Biologic (CAB) platform to develop a dual CAB T cell engager (TCE) bispecific antibody targeting Nectin-4 and CD3 receptors (CAB-Nectin-4 x CAB-CD3 bispecific antibody). The dual CAB Nectin-4 x CD3 bispecific antibody was engineered to bind with high affinity to both Nectin-4 and CD3 receptor antigens under conditions that mimic the acidic tumor microenvironment, but with lower binding activity in physiological (alkaline) conditions. In vitro and in vivo efficacy data for a dual-CAB Nectin-4 x CD3 bispecific antibody will be presented. Our data will demonstrate that the dual-CAB bispecific antibody promotes cytotoxicity of Nectin-4-expressing cancer cells in vitro and induces complete tumor regression in vivo. Further, the dual CAB Nectin-4 x CD3 bispecific antibody has higher potency in inducing primary T cell activation measured by means of cytokine release and cancer cell cytotoxicity under acidic conditions compared to the non-CAB benchmark bispecific antibody. Citation Format: Matthew Lucas, Ana Paula Cugnetti, Haizhen Liu, Charles Xing, Jing Wang, Patricia McNeeley, Christina Wheeler, Solmarie Joyner, Kyrie Johnson, Kathryn Woodard, Wei Zhou, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. A novel dual CAB nectin-4 x CD3 bispecific antibody targeting solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1879.
Abstract 6154: Imipramine induces apoptosis and inhibits metastasis via suppression of EGFR signaling pathway in bladder cancer
Authors: Tsai Lin Lo, Jai-Jen Tsai, Fei-Ting Hsu, Yuan Chang
Journal: Cancer Research (2023)

Abstract Bladder cancer (BC) is one of the most common malignant diseases of the urinary system, with poor prognosis and high recurrence and metastasis rate. Recent literatures suggested that BC patients have proportionately worse depression and mental health, as well as being at increased risk of suicidal death when compared to the general population, while relatively sane BC patients have a 2.2 times higher mortality rate, which means that depression can make BC worse. Imipramine is a tricyclic antidepressant, was used to treat neuropathic pain, nocturnal enuresis, and depression. Recently, imipramine has been reported to owns anti-tumor efficacy in various type of cancer. However, the effects and underlying mechanisms of imipramine on BC is remaining unclear. First, we indicated that imipramine may induce cytotoxicity of BC by MTT assay. Flow cytometry also showed that imipramine may trigger the loss of mitochondrial membrane potential, the accumulation of oxidative stress (ROS), and the activation of cleaved-caspase-3, -8 and -9. Our western blotting assay and immunofluorescence translocation staining also verified that imipramine markedly inhibited BC progression by inhibiting both EGFR/AKT/NFΚB and EGFR/ERK/NΚB signaling pathways. Furthermore, transwell and wound healing assay indicated that imipramine effectively reduced the metastatic ability of BC. In addition, the anti-tumor effect of imipramine was also validated by MB49 bearing animal model. Most importantly biochemistry level and pathology was not affected by imipramine. In conclusion, imipramine may not only suppressed BC progression by inactivation of EGFR/AKT/NFΚB and EGFR/ERK/NFΚB signaling pathways and induction of apoptosis pathways. These results suggested that imipramine has the opportunity to be a new therapeutic strategy for BC patients. Citation Format: Tsai Lin Lo, Jai-Jen Tsai, Fei-Ting Hsu, Yuan Chang. Imipramine induces apoptosis and inhibits metastasis via suppression of EGFR signaling pathway in bladder cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6154.
Abstract 1065: Cancer-specific molecular subtypes of cholangiocarcinoma reveal unique molecular dependency with clinical relevance
Authors: Woo Young Kwon, Sung Hwan LEE
Journal: Cancer Research (2023)

Abstract Introduction: Cholangiocarcinoma is a heterogeneous tumor entity harboring distinct tumor biology and clinical phenotype according to their unique tumor microenvironment (TME), especially anatomic location in terms of intrahepatic, peri-hilar, and distal extrahepatic portion. Therefore, there is a clear unmet need for the precision strategy based on cancer-specific genomic features rather than previous molecular subtypes from bulk RNA sequencing. Methods: Comprehensive analyses were performed using the dataset from the cancer dependency map (DepMap) project, including cancer-specific molecular characterization with multi-omics data, genome-wide loss-of-function screening with CRISPR-Cas9 system, and drug sensitivity with compound screening to uncover cancer-specific molecular subtypes showing clinical relevance. The cancer-specific molecular signatures were validated in independent translational cohorts (TCGA-CHOL; n=45, ICGC-BTC; n=181, GSE132305; n=220). Results: Integrative profiling of transcriptome from bile duct cancer cell lines (n=39) from the Cancer Cell Line Encyclopedia (CCLE) revealed a total of three cancer-specific molecular subtypes showing distinct tumor biology through all omics layer as well as clinical relevance with prognostic significance. Major molecular features of each subtype were reproducible in the validation cohorts. Subtype-specific molecular biomarkers, including mutational signature and metabolites, were identified. Finally, the target drug with subtype-specific genetic dependency was analyzed to provide precision strategy according to distinct subtypes’ molecular characterization. Conclusions: Comprehensive analysis using a multi-omics dataset revealed precision strategies based on cancer-specific molecular subtypes of cholangiocarcinoma in terms of tumor classification and discriminative therapeutic chances. Prospective translational studies companion with clinical trials based on cancer-specific molecular subtypes is mandatory to establish the precision strategy for managing cholangiocarcinoma. Citation Format: Woo Young Kwon, Sung Hwan LEE. Cancer-specific molecular subtypes of cholangiocarcinoma reveal unique molecular dependency with clinical relevance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1065.
Abstract 1361: Astrocytes activate neuronal programming in melanoma brain metastases
Authors: Julia K. Farnan, Maria R. Cavallo, Edward J. Hartsough, Joshua G. Jackson
Journal: Cancer Research (2023)

Abstract Melanoma Brain Metastases (MBM) pose a major challenge for treating metastatic melanoma. Up to 70% of advanced melanoma patients develop MBM, resulting in significant morbidity and mortality. Melanocytes, the originating cell type of melanomas, are derived from neural crest cells in development. Melanoma’s proclivity to metastasize to the brain has been anecdotally connected to its neural crest origins. Recently, transcriptomic analyses have demonstrated that MBM express a neuronal-like phenotype, upregulating neural crest factors such as NCAM (Neural cell adhesion molecule), L1CAM (L1 cell adhesion molecule protein), while expressing melanocytic markers like MITF (melanocyte induction transcription factor). The activation of neuronal development programming may be a key mediator in brain-metastatic growth, and thus necessitates a better understanding of how melanoma cells adapt to the brain. Astrocytes have emerged as the major host cell type that cancer cells encounter and interact with during brain metastasis formation. Typically, astrocytes regulate brain homeostasis and support neuronal function. Their response to injury, termed reactive astrocytosis, is a process defined by increased secretion of growth factors and inflammatory cytokine production. Post-mortem analyses of MBM patients reveal perilesional reactive astrocytosis. Here we demonstrate that astrocyte reactivity promotes MBM growth, using in vitro and in vivo model systems. We identify that astrocytes secrete factors that increase tumor growth and expression of neural development factors. Moreover, pharmacological inhibition of neural development pathways, like Wnt signaling, attenuate the effects of astrocyte secreted factors. We developed a brain adapted melanoma line, D4M3a BrJ, and demonstrate the time course of astrocyte reactivity in vivo in its relationship with tumor growth. Our findings provide evidence that astrocyte reactivity promotes MBM growth and activation of neural development programming, unveiling a new therapeutic avenue for targeting the brain metastatic niche. Citation Format: Julia K. Farnan, Maria R. Cavallo, Edward J. Hartsough, Joshua G. Jackson. Astrocytes activate neuronal programming in melanoma brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1361.
Abstract 4991: Phosphorylation of MERTK is required for nuclear localization in non-small cell lung cancer (NSCLC)
Authors: K.M. Tanim, Deborah DeRyckere, Douglas K. Graham
Journal: Cancer Research (2023)

Abstract MERTK is a transmembrane receptor that belongs to the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases. The role of MERTK in cancer progression and resistance to therapies are reported in many cancer types, including non-small cell lung cancer (NSCLC). In canonical signaling, MERTK is localized at the cell membrane and mediates intracellular signal transduction pathways. Non-canonical signaling of receptor tyrosine kinases (RTKs) has been reported, including signaling which occurs when RTKs translocate to the nucleus. Our group previously reported nuclear localization of MERTK in leukemia cells and we now extend these findings to non-small cell lung cancer. We found exogenous MERTK localized to the nucleus in cells transfected with a plasmid expressing wild-type MERTK. Additionally, endogenous nuclear MERTK was phosphorylated, suggesting that MERTK may have a functional role in the nucleus. MERTK kinase inhibitor MRX-2843 modulates its nuclear translocation. Introducing point mutations to MERTK autophosphorylation sites diminished nuclear translocation in comparison to cells transfected with wild-type MERTK. Our analysis of proteins that may interact with MERTK to regulate nuclear localization and function demonstrated co-immunoprecipitation of nuclear MERTK and STAT1. Current studies are underway to further explore nuclear MERTK functions and how these roles may be modulated upon interaction with STAT1. Citation Format: K.M. Tanim, Deborah DeRyckere, Douglas K. Graham. Phosphorylation of MERTK is required for nuclear localization in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4991.